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Published on: April 16, 2015

The autoimmune suppressor Gadd45alpha inhibits the T cell alternative p38 activation pathway

Jesus M Salvador1, Paul R Mittelstadt, Galina I Belova

  • 1Gene Response Section, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.

Nature Immunology
|March 1, 2005
PubMed

Insights

Gadd45alpha protein normally prevents T cell activation via the p38 MAP kinase (MAPK) pathway. Its absence leads to spontaneous p38 MAPK activation, causing T cell hyperproliferation and lupus-like autoimmune disease in mice.

Area of Science:

  • Immunology
  • Molecular Biology
  • Cell Signaling

Background:

  • p38 MAP kinase (MAPK) is crucial in cellular responses.
  • T cells possess an alternative activation pathway involving Zap70 tyrosine kinase.
  • Gadd45alpha is a p38-binding molecule, and its deficiency is linked to autoimmune disease.

Purpose of the Study:

  • To investigate the role of Gadd45alpha in regulating p38 MAPK activity in T cells.
  • To elucidate the mechanism by which Gadd45alpha prevents T cell hyperproliferation and autoimmunity.

Main Methods:

  • Analysis of p38 MAPK activity and phosphorylation in T cells from Gadd45a(-/-) mice.
  • In vitro inhibition assays using recombinant Gadd45alpha.
  • Comparison of T cells and B cells from knockout and wild-type mice.

Main Results:

  • Resting T cells from Gadd45a(-/-) mice exhibited spontaneous p38 MAPK activation without upstream MAPK kinase involvement.
  • This spontaneous activation was due to phosphorylation of p38 at Tyr323.
  • Recombinant Gadd45alpha specifically inhibited the activity of p38 from Gadd45a(-/-) T cells in vitro.

Conclusions:

  • Gadd45alpha acts as a critical negative regulator of the alternative p38 MAPK activation pathway in T cells.
  • Loss of Gadd45alpha leads to constitutive p38 MAPK activation, resulting in T cell hyperproliferation and autoimmunity.
  • Gadd45alpha deficiency is a potential driver of lupus-like autoimmune disease through aberrant T cell signaling.

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